ClinGen Dosage Sensitivity Curation Page


Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function phenotype
PubMed ID Description
22795537 Jones et al. 2012: Describes mutations in MLL (currently known as KMT2A) in 5 of 6 individuals with hairy elbows, short stature, facial dysmorphism, and developmental delay (Wiedemann-Steiner syndrome). All five mutations were de novo; four were frameshift mutations thought to result in premature truncation, and one was a nonsense mutation. None of the observed mutations were present in dbSNP, had been observed by the 1000 Genomes Project, or were detected in 600 unrelated control exome profiles. The variants were confirmed with Sanger sequencing in the respective probands. In order "to establish whether the mutant MLL(KMT2A) alleles were subject to nonsense-mediated decay, the authors used a quantitative real-time PCR assess the total abundance of MLL(KMT2A) transcripts in primary skin fibroblast cells derived from individual WSS-3, heterozygous for the c.6913del allele. The authors observed that the level of MLL(KMT2A) transcript was reduced in comparison to unrelated healthy controls, consistent with the notion that transcripts arising from the mutant MLL(KMT2A) alleles are subject to nonsense-mediated decay."
24818805 Mendelsohn et al. 2014 identified a de novo intragenic deletion of exons 2-10 within the KMT2A (MLL) gene by whole exome sequencing. Patient presented with mild developmental delay, short stature, dysmorphic facial features, advanced bone age, renal anomalies and hypertrichosis. However, this patient has generalized hypertrichosis unlike previously reported Wiedemann-Steiner syndrome (WDSTS) patients with hypertrichosis cubiti as reported by Jones et al. further expanding the variable patterns of hypertrichosis and first reported Wiedemann-Steiner syndrome due to exonic deletion.
27759909 Sun et al. 2016 describe two males with de novo nonsense mutations in the KMT2A gene detected by whole exome sequencing. Both nonsense mutations were absent in the 1000 genomes project ExAC, EVS and in an inhouse database. Most of the males phenotype was concordant with WDSTS however, both lacked hypertrichosis cubiti but did show generalized hypertrichosis. A comparison of the two reported patients to previously reported and a common phenotype that included postnatal growth retardation, developmental delay, intellectual disability, distinct dysmorphic features and generalized hypertrichosis.

Evidence for Triplosenstive Phenotype

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.